摘要
目的探讨临床治疗剂量喹硫平体内代谢机制。方法19例病人均经历多剂量单独使用喹硫平和多剂量喹硫平与红霉素合用两个周期。同时,给予单剂量的咪达唑仑测定酶活性。在一定的时间间隔内采集血样,用HPLC-MS/ESI+测定喹硫平及其3个代谢产物浓度;用HPLC-UV测定咪达唑仑及其代谢产物浓度。结果喹硫平与红霉素联用后,CYP3A4活性显著下降;喹硫平的ρmSSax,AUCS0-S24和t1/2显著增加,CL/F显著下降,AUC0S-S24和CL/F的改变量分别与CYP3A4活性改变量负和正相关;磺氧化喹硫平的ρmSSax,AUCS0-S24显著减少,t1/2显著延长,t1/2的改变量与CYP3A4活性改变量正相关;7-羟基喹硫平的ρmSSax和AUC0S-S24没有显著性改变,t1/2显著延长并与CYP3A4活性相关;7-羟基-氮去烷基-喹硫平的t1/2没有显著性改变,ρSmSax和AUC0S-S24显著下降,AUC0SS-24的改变量与CYP3A4活性改变量正相关。结论喹硫平的磺氧化和氮去烷基化主要由CYP3A4催化,7-羟基化不是主要由CYP3A4催化,其中磺氧化是喹硫平的体内主要代谢途径。
OBJECTIVE To study the metabolic mechanism of quetiapine at clinical therapeutic dose. METHODS Nineteen patients received multiple doses of quetiapine （200 mg, twice daily） with or without concomitant erythromycin （500 mg, three times daily）. At the same time, midazolam was given to detect the enzyme activity. Blood samples were collected at specified time intervals. Concentrations of quetiapine and some metabolites in plasma were assayed by HPLC-MS/ESI^＋ , as well as midazolam and its metabolite by HPLC-UV. RESULTS In the presence of erythromycin,the activity of CYP3A4 decreased significantly. For quetiapine, the ρmax^SS, AUC（0-24）^SS and t（1/2） elevated significantly, the ratio of CL/F decreased significantly, the variation of AUC（0-24）^SS and CL/F was significantly negative and positive correlated to that of CYP3A4 activity respectively. For quetiapine sulfoxlde, the ρmax^SS and AUC（0-24）^SS decreased significantly ,the t（1/2） elevated significantly, and the variation of t（1/2） was significantly positive correlated to that of CYP3A4 activity. For 7-hydroxy-quetiapine, the ρmax^SS and AUC（0-24）^SS showed no statistical change, the t（1/2） elevated significantly and was closely correlated to CYP3A4 ρmax^SS, AUC（0-24）^SS decreased significantly, and the activity. For 7-hydroxy-N-desalkyl-quetiapine, the t（1/2） showed no statistical cnange ρmax^SS and AUC（0-24）^SS decreased significantly, and the variation of AUC（0-24）^SS was significantly positive correlated to that of CYP3A4 activity. CONCLUSION The major metabolic pathway of quetiapine is sulfoxidation. CYP3A4 is the primary enzyme responsible for the CYP-mediated metabolism of quetiapine at clinical therapy dosage in vivo. Quetiapine sulfoxidation and N-dealkylation are mainly catalyzed by CYP3A4. 7-Hydroxylation of quetiapine is not mainly catalyzed by CYP3A4.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2007年第20期1564-1567,共4页
Chinese Pharmaceutical Journal
